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The role of TMEM26 in disrupting tight junctions and activating NF-κB signaling to promote epithelial-mesenchymal transition in esophageal squamous cell carcinoma
Guohu Hana,b, Shuangshuang Zhoua, Junjun Shena, Yuanyuan Yanga, Xuyu Biana, Yahu Lia, Rui Lingc, Rongrui Lianga,d, Min Taoa,d,
Corresponding author
taomin@suda.edu.cn

Corresponding author at: Department of Oncology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
a Department of Oncology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China
b Department of Oncology, Jingjiang People's Hospital Affiliated with Yangzhou University, Jingjiang, Jiangsu, China
c Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
d Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Introduction</span><p id="para0008" class="elsevierStylePara elsevierViewall">Esophageal Carcinoma &#40;EC&#41; is one of the most frequently diagnosed tumors in the digestive tract and is mainly classified into two types of EC&#58; Esophageal Squamous Cell Carcinoma &#40;ESCC&#41; and Esophageal Adenocarcinoma &#40;EAC&#41;&#46; ESCC is the predominant subtype of EC in Asians&#44; which is mainly caused by smoking&#44; alcohol consumption&#44; hot drinks&#44; and other poor dietary habits&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> ESCC is characterized by low differentiation&#44; which drives the malignant transformation of esophageal epithelial cells to initiate its pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a></p><p id="para0009" class="elsevierStylePara elsevierViewall">Another known characteristic of ESCC is the high rate of metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> In general&#44; metastatic ESCC at an early stage can be treated with surgery combined with chemotherapy and radiation therapy&#46; Unfortunately&#44; most ESCC cases are diagnosed at an advanced stage&#59; hence&#44; the prognosis is always poor&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> Despite the surgical technique and perioperative management advances&#44; recurrence&#44; and distant metastasis of ESCC are frequently reported&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> Therefore&#44; the mechanisms orchestrating ESCC metastasis should be understood&#44; where the Epithelial-Mesenchymal Transition &#40;EMT&#41; program plays a critical role&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">EMT is an important process for cancer cells to acquire a metastatic phenotype <a class="elsevierStyleCrossRefs" href="#bib0006"><span class="elsevierStyleSup">6&#8211;8</span></a>&#46; A plethora of signaling pathways is involved in the control of EMT in ESCC&#46; For example&#44; cell division cycle-associated 7&#44; the gene amplified in ESCC&#44; enhanced the metastasis and invasion of ESCC cell lines both <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span> by activating TGF-&#946; signaling to facilitate EMT&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> Kinesin Family member C3 &#40;KIFC3&#41;&#44; a kinesin superfamily protein&#44; was upregulated in ESCC tissues and associated with poor prognosis in patients with ESCC&#44; and mechanistic studies indicated that KIFC3 promoted proliferation&#44; migration&#44; and invasion of ESCC via &#946;-catenin signaling and EMT&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> YAP activation driven by C12orf59&#44; a novel cancer-related factor prominently higher in both tumor tissues and most ESCC cell lines&#44; contributes to the EMT of ESCC&#44; and thereby&#44; combined treatment of C12orf59&#44; and YAP inhibitors could be developed as a therapeutic strategy for metastatic ESCC&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> Furthermore&#44; a recent study revealed that neuron-specific gene family member 1 may amplify the ERK signaling pathway to promote ESCC cell EMT&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> Hence&#44; uncovering the molecules driving the EMT process can help identify therapeutic strategies and prolong the survival of patients with metastatic ESCC&#46;</p><p id="para0011" class="elsevierStylePara elsevierViewall">Epithelial cells contain several classes of cell-cell junctions&#58; adherens junction&#44; Tight Junction &#40;TJ&#41;&#44; desmosomes&#44; and gap junction&#46; TJ consisted of multiple proteins&#44; such as claudin&#44; occludin&#44; and Zonula Occludens-1&#47;2&#47;3 &#40;ZO-1&#47;2&#47;3&#41;&#46; TJ organizes the junctional complex on the apical side between neighboring epithelial cells and plays supportive roles in cell architecture&#46; TJs are also important for maintaining cell polarity and substance passing between epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Increasing evidence supports the well-established functional role of TJ proteins in cancer pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> The intracellular regions of TJ proteins bind to cytoskeletal elements and signaling molecules&#44; acting downstream of certain essential signaling pathways to regulate cell migration&#44; proliferation&#44; and differentiation&#44; all of which are important cancer hallmarks essential for tumor growth and metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a></p><p id="para0012" class="elsevierStylePara elsevierViewall">To initiate the EMT process&#44; the contact between epithelial cells must be broken down&#44; including the disruption of TJ structures&#46; TJ disassembly promotes the loss of cell polarity and reorganization of the cytoskeleton to potentiate cell migration and cancer metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Several studies reported the role of TJ in the EMT of cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> The lncRNA-NEAT1 was induced by the carcinogen arecoline to downregulate ZO-1 expression and destabilized TJ assembly&#44; which enabled the EMT initiation in head and neck cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> The flavonoid compounds&#44; baicalin&#44; and baicalein&#44; disrupted the TJ structure by targeting the first PDZ domain of ZO-1 to suppress its interaction with occludin&#44; resulting in EMT-like morphological changes in the Madin&#8211;Darby canine kidney II cells&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> In colorectal cancer cells&#44; the tumor-related mutant &#946;-catenin downregulated the expression of ZEB1 transcription factor-controlled TJ proteins&#44; claudin-7&#44; and E-cadherin&#44; to impair the TJ structure&#44; resulting in increased cell motility and EMT progression&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> However&#44; whether TJ impairment is involved in the EMT of ESCC remains to be elucidated&#46; Moreover&#44; whether a membrane protein could directly impair the TJ structure &#40;without affecting the TJ protein expression&#41; to promote EMT progression remains elusive&#46;</p><p id="para0013" class="elsevierStylePara elsevierViewall">The Transmembrane protein 26 &#40;TMEM26&#41; gene encodes a protein containing multiple transmembrane fragments&#46; It was detected specifically in brown and beige adipocytes and was&#44; therefore&#44; considered the marker for these cells&#46;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> Information on the function of this putative plasma membrane protein in the literature is extremely limited&#46; Intrigued by the novelty of this gene and its possible involvement in ESCC&#44; this study aimed to evaluate the role of TMEM26 in ESCC tissues and a series of ESCC cell lines&#46; Immunostaining indicated elevated TMEM26 expression in ESCC tumors&#46; Various ESCC cell lines showed a high TMEM26 expression&#44; where its plasma membrane localization was confirmed&#46; The RNAi depletion of TMEM26 in TMEM26-high ESCC cells suppressed EMT-related alterations&#44; including invasion&#44; migration&#44; and marker gene expression&#46; Conversely&#44; TMEM26 overexpression in TMEM26-low ESCC cells promoted these EMT-related alterations&#46; Interestingly&#44; TMEM26 depletion or overexpression did not affect cell growth&#44; indicating its specific involvement in the EMT process&#46; The animal study demonstrated the contributive role of TMEM26 in metastatic ESCC&#46; Mechanistically&#44; TMEM26 promoted NF-&#954;B signaling to accelerate EMT in ESCC cells&#46; The plasma membrane presentation and TJ protein assembly were impaired by TMEM26&#44; which was likely to be another mechanism for EMT regulation by TMEM26 in ESCC&#46; Therefore&#44; TMEM26 disrupted TJ formation and promoted NF-&#954;B signaling during the EMT activation in ESCC&#46; The development of TMEM26-targeting drugs might offer an innovative line of therapies for ESCC&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Cell lines&#44; reagents&#44; and antibodies</span><p id="para0014" class="elsevierStylePara elsevierViewall">ESCC cell lines &#40;KYSE150&#44; KYSE270&#44; KYSE450&#44; TE4&#44; and TE8&#41; and a normal esophageal epithelial cell line &#40;HET-1A&#41; were obtained from ATCC &#40;MA&#44; USA&#41;&#46; The Roswell Park Memorial Institute &#40;RPMI&#41;-1640 medium&#44; 5-diphenyltetrazolium bromide &#40;MTT&#41; kit&#44; and 4&#8242;&#44;6-Diamidino-2-Phenylindole &#40;DAPI&#41; stain solution were supplied by Sigma &#40;MO&#44; USA&#41;&#46; Lipofectamine 3000 reagents and Bicinchoninic Acid &#40;BCA&#41; kit were purchased from Thermo Scientific &#40;CA&#44; USA&#41;&#46; Fetal Bovine Serum &#40;FBS&#41; was procured from GIBCO &#40;CA&#44; USA&#41;&#46; Horseradish Peroxidase &#40;HRP&#41;-conjugated goat anti-rabbit&#47;mouse antibodies were obtained from Cell Signaling Technology &#40;MA&#44; USA&#41;&#46; Alexa Fluor 488 or 555 donkey anti-rabbit&#47;mouse secondary antibodies were purchased from Beyotime &#40;Shanghai&#44; China&#41;&#46; Information on primary antibodies used in this study is listed in Table S1&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Patients and ESCC specimen collection</span><p id="para0015" class="elsevierStylePara elsevierViewall">ESCC biopsy specimens and non-cancerous biopsy samples from the same patients &#40;<span class="elsevierStyleItalic">n</span> &#61;&#8201;40&#41; were collected from Jingjiang People&#39;s Hospital Affiliated with Yangzhou University&#46; All donors provided signed written informed consent&#46; The experimental protocol was approved by the ethics committee of Jingjiang People&#39;s Hospital Affiliated with Yangzhou University&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Immunohistochemistry</span><p id="para0016" class="elsevierStylePara elsevierViewall">ESCC tumor specimens were incubated at 60&#160;&#176;C for 2&#160;h at pretreatment with dimethyl benzene for dewaxing&#46; The sections were then hydrated with a gradient of alcohol and washed with double distilled water &#40;ddH<span class="elsevierStyleInf">2</span>O&#41;&#46; Subsequently&#44; the sections were fixed with 3&#37; hydrogen peroxide for 15&#160;min and then washed with Phosphate-Buffered Saline &#40;PBS&#41; three times at Room Temperature &#40;RT&#41;&#46; Then&#44; the sections were incubated with primary TMEM26 antibodies at 37&#160;&#176;C for 30&#160;min and at 4&#160;&#176;C overnight&#46; Afterward&#44; the secondary antibody was added and incubated for 30&#160;min at 37&#160;&#176;C&#46; Next&#44; the sections were sequentially incubated with HRP-labeled avidin for 30&#160;min at 37&#160;&#176;C and reacted with domain antibodies for 3&#8211;10&#160;min before the reaction was stopped by ddH<span class="elsevierStyleInf">2</span>O&#46; Counterstaining was performed with hematoxylin and then dehydration&#46; The sections were finally examined under a microscope &#40;BX51&#44; Olympus&#44; Japan&#41;&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">The liver metastatic murine model</span><p id="para0017" class="elsevierStylePara elsevierViewall">The Institutional Animal Care and Use Committee at the Affiliated Hospital of Jiangsu University approved all animal procedures in this study&#46; Twenty BALB&#47;c nude male mice were purchased from Cavens Laboratory Animal Inc&#46; &#40;<a href="http://www.cavens.com.cn/">http&#58;&#47;&#47;www&#46;cavens&#46;com&#46;cn&#47;</a>&#41;&#46; All mice were maintained under specific-pathogen-free conditions and subjected to 1-week acclimation before starting animal experiments&#46;</p><p id="para0018" class="elsevierStylePara elsevierViewall">To evaluate the ESCC cell metastasis to the liver&#44; the mice were divided into four groups&#58; si-NC&#44; si-TMEM26 &#35;2&#44; vector&#44; and TMEM26 OE&#46; Briefly&#44; ESCC cells &#40;KYSE270 and KYSE150&#41; with either TMEM26 knockdown or overexpression were injected into the portal vein of the mouse liver&#46; ESCC cells with si-NC transfection or vector injected into the portal vein of the liver served as the control&#46; At 28 days post-injection&#44; liver tissues were dissected&#44; and subjected to hematoxylin and eosin staining to examine liver metastasis&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Cell culture and transfection</span><p id="para0019" class="elsevierStylePara elsevierViewall">KYSE150&#44; KYSE270&#44; KYSE450&#44; TE4&#44; and TE8 cells were cultured in a 10&#160;cm dish with RPMI-1640 and 10&#37; FBS in an incubator at 37&#176; and 5&#37; CO<span class="elsevierStyleInf">2</span>&#46; siRNA transfection &#40;with sequences listed in Table S2&#41; was conducted using Lipofectamine 3000&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">MTT assay for cell viability</span><p id="para0020" class="elsevierStylePara elsevierViewall">The cells &#40;1&#160;&#215;&#160;10<span class="elsevierStyleSup">4</span> cells&#47;well&#41; were grown overnight in 96-well plates&#46; The volume of the culture medium was 100&#160;&#956;L per well&#46; After overnight incubation&#44; 10&#160;&#956;L of MTT solution was pipetted into each well and incubated for another 4&#160;h&#46; Subsequently&#44; the medium was discarded&#44; and formazan crystals were dissolved by adding 150&#160;&#956;L of dimethyl sulfoxide&#46; The absorbance was read at 570&#160;nm wavelength using a microplate instrument &#40;Thermo Scientific&#41;&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Wound healing assay</span><p id="para0021" class="elsevierStylePara elsevierViewall">The assay was performed with the CytoSelec 24-well Wound Healing Assay Kit &#40;BIOCAT GmbH&#44; Heidelberg&#44; Germany&#41; following the instruction provided with the kit&#46; Briefly&#44; 250&#160;&#181;L of cell suspension &#40;2&#160;&#215;&#160;10<span class="elsevierStyleSup">5</span> cells&#47;mL&#41; was added on each side of the insert&#46; Cells were cultured until they formed a monolayer around the insert &#40;about 24&#160;h&#41;&#46; Next&#44; the inserts were removed from the wells&#44; leaving a precise open &#8220;wound field&#8221; between the cells&#46; The wells were washed twice with PBS and then fulfilled with 500&#160;&#181;L of a fresh culture medium&#46; Images of the wounded area containing migrated cells were taken at 0 and 24&#160;h using an Olympus BX51 microscope&#44; whereas measurements were performed using Image J&#46;</p><p id="para0022" class="elsevierStylePara elsevierViewall">Cell migration was quantified after determining the surface area of the defined wound area &#40;total surface area&#41; and migrated cells into the wounded area &#40;migrated cell surface area&#41;&#58; Percentclosure&#40;&#37;&#41;&#61;Migratedcellsurfacearea&#47;Totalsurfacearea&#215;100&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Transwell invasion assay</span><p id="para0023" class="elsevierStylePara elsevierViewall">The invasion of ESCC cells was evaluated with the 8&#160;&#956;m-pore Transwell &#40;Corning&#44; MA&#44; USA&#41;&#46; In brief&#44; 1&#160;&#215;&#160;10<span class="elsevierStyleSup">5</span> cells in 200&#160;&#956;L of the FBS-free medium were added to the matrigel-coated upper chamber&#44; whereas 700&#160;&#956;L of the medium containing 10&#37; FBS was added to the lower chambers&#46; After 48&#160;h incubation&#44; non-invaded cells were removed by cotton swab&#44; whereas invaded cells were fixed in 4&#37; methanol for 30&#160;min&#44; dyed by 0&#46;1&#37; crystal violet &#40;Beyotime&#41; for 20&#160;min&#44; and counted under the Olympus BX51 microscope&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Western blotting</span><p id="para0024" class="elsevierStylePara elsevierViewall">The whole cell lysate was generated in a pre-cold radioimmunoprecipitation assay buffer&#46; Protein concentration was measured using the BCA kit with the protocol provided by manufacturers&#46; The protein extract was resolved on the 10&#8211;15&#37; sodium dodecyl-sulfate polyacrylamide gel electrophoresis gel and transferred and electro-blotted onto a nitro-cellular membrane &#40;Millipore&#41;&#46; The membrane with transient wash was then blocked by incubation with 5&#37; non-fat milk and incubated with primary antibodies at 4&#160;&#176;C for 16&#160;h&#46; Secondary antibodies with HRP conjugation were used for chemiluminescent signal determination&#46; Immunoreactive signals were assessed using a kit of enhanced chemiluminescence chromogenic substrates &#40;Bio-Rad&#44; Hercules&#44; CA&#44; USA&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Immunofluorescent staining</span><p id="para0025" class="elsevierStylePara elsevierViewall">ESCC cells growing on glass slides were washed in PBS&#44; fixed in immunofluorescent staining fixation &#40;Beyotime&#41; for 10&#160;min&#44; permeabilized with 0&#46;5&#37; Triton-X100 for 10&#160;min&#44; and blocked for 1&#160;h at RT with 5&#37; bovine serum albumin and incubated with primary antibodies at 4&#160;&#176;C overnight&#46; Cells were rinsed three times in PBS and sequentially incubated with the secondary antibody for 1h at RT&#46; Cells were finally washed in PBS to remove the antibody mixture&#46; An anti-fade mounting medium was used with DAPI for samples&#46; Fluorescence images were acquired using an Olympus BX51 microscope&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Statistical analysis</span><p id="para0026" class="elsevierStylePara elsevierViewall">Data are presented as means &#177; Standard Deviations &#40;S&#46;D&#46;s&#41;&#46; Statistical analysis was conducted with GraphPad Prism 8&#46;4&#46;2 software &#40;San Diego&#44; USA&#41;&#46; A two-tailed unpaired Student&#39;s <span class="elsevierStyleItalic">t</span>-test was performed to compare the two groups&#46; A one-way analysis of variance combined with Tukey&#39;s post-multiple tests was conducted to compare multiple groups&#46;</p></span></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Results</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">Elevated TMEM26 expression in ESCC</span><p id="para0027" class="elsevierStylePara elsevierViewall">To determine the TMEM26 expression in human ESCC&#44; immunohistochemical staining for TMEM26 was performed for slices from the tumor and adjacent normal tissues from patients with ESCC&#46; Evidently&#44; the tumor tissues exhibited higher staining &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1A</a>&#41; and contained a higher number of TMEM26-positive cells by quantification &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1B</a>&#41;&#46; This result was suggestive of a supportive role of TMEM26 in ESCC progression&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0028" class="elsevierStylePara elsevierViewall">A collection of ESCC cell lines &#40;KYSE150&#44; KYSE270&#44; KYSE450&#44; TE4&#44; and TE8&#41; and a normal esophageal epithelial cell line &#40;HET-1A&#41; were examined with western blotting to assess the number of TMEM26&#46; TMEM26 expression level was higher in all included ESCC cell lines than that in HET-1A cells&#44; and a clear cell-to-cell variability was observed in TMEM26 expression &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2A</a>&#41;&#46; The KYSE270 and TE8 showed a higher number of TMEM26 and were selected to further examine TMEM26 depletion&#46; Conversely&#44; KYSE150&#44; and KYSE450 showed a lower number of TMEM26 and were selected to further evaluate TMEM26 ectopic overexpression&#46; An elevated TMEM26 expression in KYSE270 and TE8 cells was verified with immunofluorescent staining&#44; where the cell membrane localization of TMEM26 was clearly observed &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2B</a>&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">Silencing TMEM26 blocked the EMT-associated processes of ESCC</span><p id="para0029" class="elsevierStylePara elsevierViewall">Suspecting TMEM26 as a critical factor involved in the EMT of ESCC&#44; the high TMEM26 expressions in ESCC cells&#44; KYSE270&#44; and TE8&#44; were examined to assess the effects of TMEM26 depletion&#46; Transfection of siRNA targeting TMEM26 gene &#40;three independent targets&#41; efficiently downregulated TMEM26 expression in these two cells&#44; as detected in western blotting &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3A</a>&#41;&#46; In both KYSE270 and TE8&#44; TMEM26 RNAi cells displayed altered invasion capability compared with control cells&#44; i&#46;e&#46;&#44; lower number of invaded cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3B</a>&#41;&#46; Consistent with the Transwell assay&#44; the wound healing assay for cells was performed to determine the capability of migration and invasion&#46; In both KYSE270 and TE8&#44; the migration of TMEM26 RNAi cells was slower than that of the control cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3C</a>&#41;&#44; which was supported by statistical analysis with repeated experiments &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3C</a>&#41;&#46; The changed morphology and migration and invasion ability could increase from reversed EMT&#59; thus&#44; marker proteins of EMT were examined using western blotting in TMEM26 RNAi or control KYSE270 and TE8 cells&#46; Four mesenchymal markers &#40;twist&#44; snail&#44; N-cadherin&#44; and vimentin&#41; were downregulated&#44; whereas the epithelial marker &#40;E-cadherin&#41; was upregulated in TMEM26 RNAi KYSE270 and TE8 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3D</a>&#41;&#44; indicating the reversed EMT process in TMEM26-depleting ESCC cells&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">TMEM26 overexpression aggravated EMT-associated processes of ESCC</span><p id="para0030" class="elsevierStylePara elsevierViewall">Consistent with findings from TMEM26 RNAi cells&#44; the effects of TMEM26 overexpression in ESCC cells with high TMEM26 expression&#44; KYSE150&#44; and KYSE450&#44; were also examined&#46; Lentiviral transfection of the TMEM26 plasmid resulted in efficient TMEM26 overexpression in KYSE150 and KYSE450 cells&#44; as shown by western blotting detection &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4A</a>&#41;&#46; In both KYSE150 and KYSE450&#44; the invasive ability of TMEM26-overexpressing cells was stronger than that of control cells &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4B</a>&#41;&#46; Consistent with the observation of invasion&#44; the wound healing assay for cells indicated that TMEM26-overexpressing cells in both KYSE150 and KYSE450 displayed accelerated migration compared with control cells &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4C</a>&#41;&#44; a finding supported by statistical analysis with repeated experiments &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4C</a>&#41;&#46; The EMT marker proteins were also examined by western blotting in TMEM26-overexpressing or control KYSE150 and KYSE450 cells&#46; In the TMEM26-overexpressing cells&#44; the expression of twist&#44; snail&#44; N-cadherin&#44; and vimentin was significantly elevated&#44; whereas that of E-cadherin was downregulated &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4D</a>&#41;&#46; Taken together&#44; the number of TMEM26 determined the EMT process of ESCC cells&#44; indicating that higher TMEM26 enhanced EMT&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia><p id="para0031" class="elsevierStylePara elsevierViewall">To understand whether TMEM26 is involved in ESCC cell proliferation that influences cell migration and invasion&#44; an MTT assay was also carried out after TMEM26 RNAi or overexpression in ESCC cells&#46; In KYSE270 and TE8&#44; siRNA knockdown of TMEM26 &#40;three independent targets&#41; did not show an observable difference in the growth curve compared with siRNA control cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5A</a>&#41;&#46; Similarly&#44; TMEM26 overexpression in KYSE150 and KYSE450 cells did not alter the growth rate of the cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5B</a>&#41;&#46; Therefore&#44; TMEM26 did not contribute to the proliferation or death of ESCC cells&#44; and its action in EMT should be considered differently&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">TMEM26 contributes to ESCC metastasis to the liver</span><p id="para0032" class="elsevierStylePara elsevierViewall">Along with <span class="elsevierStyleItalic">in vitro</span> EMT-related assays&#44; the role of TMEM26 in ESCC metastasis was monitored on the liver metastatic murine model&#46; Consistent with the <span class="elsevierStyleItalic">in vitro</span> analysis&#44; the aggressive ability of KYSE270 cells to the liver was weakened after TMEM26 RNAi&#44; as indicated by the lower number of metastases and reduced area of cancerous nests in the liver compared with the control &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6A&#44;B</a>&#41;&#46; Conversely&#44; TMEM26-overexpressing KYSE150 cells exhibited a more aggressive ability to the liver&#44; as indicated by a higher number of metastases and the larger area of cancerous nests in the liver compared with the control &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6C&#44;D</a>&#41;&#46; These results further confirmed the essential role of TMEM26 in ESCC metastasis&#44; which is mediated by EMT&#46;</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">TMEM26 promoted NF-&#954;B signaling and is involved in the EMT of ESCC</span><p id="para0033" class="elsevierStylePara elsevierViewall">Motivated by the report that NF-&#954;B signaling was involved in the EMT of breast cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a>&#44; the present study examined the effects of TMEM26 on NF-&#954;B signaling and whether this signaling mediates the action of TMEM26 in the EMT of ESCC cells&#46; In TMEM26-overexpressing KYSE270 and TE8 cells&#44; siRNA knockdown of TMEM26 &#40;three independent targets&#41; did not show an observable difference in the total number of p65 and I&#954;B&#945;&#44; whereas the p65 and I&#954;B&#945; phosphorylation was dramatically declined&#44; indicating an inhibited NF-&#954;B signaling by TMEM26 knockdown &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7A</a>&#41;&#46; Consistent with this&#44; TMEM26 overexpression in low TMEM26-expressing KYSE150 and KYSE450 cells resulted in elevated p65 and I&#954;B&#945; phosphorylation&#44; whereas the total amount of p65 and I&#954;B&#945; remained comparable &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7B</a>&#41;&#46; PS1145 is a specific small-molecule IKK inhibitor used to inactivate NF-&#954;B signaling in cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> The treatment with PS1145 for KYSE150 and KYSE450 cells efficiently blocked the upregulation of twist expression through TMEM26 overexpression &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 7C</a>&#41;&#44; demonstrating the indispensable role of NF-&#954;B signaling in the EMT of ESCC cells&#46; Corroborated with this&#44; wound healing and Transwell assays showed that PS1145 intervention effectively blocked the TMEM26 overexpression-induced promotion in the migration and invasion of KYSE150 and KYSE450 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7D</a> and <a class="elsevierStyleCrossRef" href="#fig0007">E</a>&#41;&#46;</p><elsevierMultimedia ident="fig0007"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">TMEM26 impaired TJ to support EMT of ESCC</span><p id="para0034" class="elsevierStylePara elsevierViewall">In addition to the finding that TMEM26 activated the NF-&#954;B signaling to promote EMT&#44; exploring the direct role of TMEM26 in the TJ complex assembly at the plasma membrane would be beneficial&#44; which would also affect the EMT process&#46; Immunofluorescent staining for three TJ proteins&#44; claudin-1&#44; occludin&#44; and ZO-1&#44; with specific antibodies&#44; confirmed their plasma membrane localization &#40;<a class="elsevierStyleCrossRef" href="#fig0008">Figs&#46; 8 and</a> S1&#41;&#46; Compared with the siRNA control&#44; the TE8 cells with siRNA knockdown of TMEM26 &#40;three independent targets&#41; demonstrated a significantly elevated intensity of claudin-1&#44; occludin&#44; and ZO-1 expression &#40;<a class="elsevierStyleCrossRef" href="#fig0008">Fig&#46; 8</a>A and B&#41;&#46; In parallel&#44; very similar&#44; albeit weaker&#44; effects of TMEM26 RNAi on the elevation of claudin-1&#44; occludin&#44; and ZO-1 signals were observed in KYSE270 cells &#40;Fig&#46; S1 A and B&#41;&#46; Consistent with the findings from TE8 and KYSE270 cells&#44; the TJ protein alteration was also observed in KYSE150 cells with TMEM26 overexpression&#46; The intensity of claudin-1&#44; occludin&#44; and ZO-1 expressions was all significantly reduced &#40;<a class="elsevierStyleCrossRef" href="#fig0008">Fig&#46; 8</a>C and D&#41;&#46; Consistently&#44; TMEM26 overexpression in KYSE450 cells resulted in a lower intensity of claudin-1&#44; occludin&#44; and ZO-1 expressions &#40;Fig&#46; S1C and D&#41;&#46; Taken together&#44; TMEM26 directly interfered with the TJ complex assembly in ESCC cells&#44; which could be an upstream factor of the EMT process&#46;</p><elsevierMultimedia ident="fig0008"></elsevierMultimedia></span></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Discussion</span><p id="para0035" class="elsevierStylePara elsevierViewall">As a devastating disease&#44; esophageal cancer is the 6th most common cause of cancer deaths worldwide&#46; China is experiencing an increasing health burden from EC&#44; currently accounting for &#62; 50&#37; of the global cases&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> EC is classified into two subtypes with distinct histopathological features&#58; ESCC and EAC&#46; ESCC is more frequently diagnosed in East Asia&#44; whereas EAC is more common in Western countries&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> Despite the rapid progress of surgery&#44; chemotherapy&#44; radiation therapy&#44; molecular targeted therapy&#44; and combinatorial therapies for ESCC&#44; its prognosis remains poor&#44; with an extremely low overall 5-year survival rate&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> The main limiting factor for efficient ESCC treatment is the high incidence rate of metastasis&#44; including the lymph nodes&#44; lungs&#44; liver&#44; bones&#44; adrenal glands&#44; and brain&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> Therefore&#44; beneficial therapeutic outcomes can be achieved through understanding the molecular and cellular mechanisms involved in metastasis&#44; particularly the EMT in ESCC&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">To elucidate the EMT mechanisms in ESCC&#44; this study focused on TMEM26&#44; a novel gene encoding a putative plasma membrane protein with multiple transmembrane domains&#46; By examining TMEM26 in the ESCC and para-tumor control tissues&#44; TMEM26 expression was elevated in the ESCC tumor&#46; In addition&#44; a series of ESCC cell lines showed high TMEM26 expression&#44; where its plasma membrane localization was confirmed&#46; The critical role of TMEM26 in promoting EMT was indicated by the invasion in Transwell assay&#44; migration in wound healing assay&#44; and expression of mesenchymal marker genes in either TMEM26 silencing or overexpressing ESCC cells&#46; Moreover&#44; <span class="elsevierStyleItalic">in vivo</span> study was also conducted and verified the critical role of TMEM26 in ESCC metastasis&#46; Interestingly&#44; the cell growth did not exhibit a similar change with TMEM26 knockdown or overexpression&#44; indicating distinct mechanisms for EMT and proliferation&#47;cell death controls in ESCC cells&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">A plethora of signaling pathways mediated the EMT of cancer cells&#44; including the prototypical proinflammatory NF-&#954;B signaling pathway&#46; The nuclear translocation of NF-&#954;B p65 can induce the transcription of several genes involved in EMT induction&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> The pterostilbene-isothiocyanate&#44; a pterostilbene derivative&#44; reverted the EMT in breast cancer metastatic cell line &#40;MDA-MB-231&#41; and <span class="elsevierStyleItalic">in vivo</span> 4T1-cell-induced metastatic mice model&#44; by preventing the IKK complex&#44; central to NF-&#954;B activation&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> In normal breast epithelial and breast cancer cells&#44; both IKK-&#946; and NF-&#954;B p65 were required for TNF-&#945;-induced Twist1 expression&#44; suggesting the involvement of canonical NF-&#954;B signaling in EMT in these cells&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> Isoimperatorin&#44; the <span class="elsevierStyleItalic">Angelica dahurica</span> derivative&#44; inhibited cell migration&#44; invasion&#44; and proliferation by inactivating NF-&#954;B signaling in colorectal and hepatocellular carcinoma cells&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Cytidine monophospho-N-acetylneuraminic acid hydroxylase pseudogene&#44; overexpressed in gastric cancer and associated with poor prognosis&#44; enhanced the p65 expression to activate the NF-&#954;B pathway&#44; which then increased the amount of snail&#44; the key transcription factor for EMT&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> Moreover&#44; homeobox D11 has been reported to activate the NF-&#954;B signaling pathway&#44; thereby promoting the malignant characteristics of ESCC&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> Based on these previous findings&#44; whether TMEM26 regulates the EMT in ESCC cells through the NF-&#954;B pathway was determined&#46; Detection of altered p65 and I&#954;B&#945; phosphorylation in ESCC cells with either TMEM26 knockdown or overexpression demonstrated the activating role of TMEM26 in the NF-&#954;B pathway in ESCC cells&#46; Notably&#44; the treatment with PS1145&#44; a specific small-molecule IKK inhibitor&#44; efficiently blocked the promotion of EMT transcription factor expression&#44; cell migration&#44; and invasion induced by TMEM26&#44; demonstrating the indispensable role of NF-&#954;B signaling in the EMT of ESCC cells&#46;</p><p id="para0038" class="elsevierStylePara elsevierViewall">TJs and signaling pathways initiated by TJs are attractive targets for cancer treatments&#46; Claudin 1 TJ protein has been recently reported to mediate RNA-binding protein LIN28B to promote invasion and liver metastasis of colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> Therefore&#44; TJ protein inhibitors and monoclonal antibodies may be employed to suppress EMT and metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> By observing the molecular architecture&#44; most TJ complexes were found to contain membrane-attached cytoplasmic plaques that regulate junction assembly and were composed of multivalent scaffold proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> Recently&#44; TJ assembly at the plasma membrane was reportedly governed by phase separation&#44; a process by which a well-mixed solution of macromolecules &#40;e&#46;g&#46;&#44; TJ proteins&#41; spontaneously separates into a dense and a dilute phase&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a> Therefore&#44; it should be determined whether TMEM26 exerts direct effects on TJ assembly at the plasma membrane&#46; By examining multiple ESCC cells&#44; with either TMEM26 knockdown or overexpression&#44; TMEM26 effectively suppressed the plasma membrane presentation and TJ protein assembly&#46;</p><p id="para0039" class="elsevierStylePara elsevierViewall">Collectively&#44; the present study determined the TMEM26 elevation in ESCC tumors and various ESCC cell lines&#44; where the plasma membrane localization of TMEM26 was also confirmed&#46; The RNAi depletion of TMEM26 in ESCC cells suppressed EMT-related alterations&#44; including invasion&#44; migration&#44; and marker gene expression&#46; Conversely&#44; TMEM26 overexpression in ESCC cells promoted these EMT-related alterations&#46; Mechanistically&#44; TMEM26 promoted NF-&#954;B signaling to accelerate EMT in ESCC cells&#46; The plasma membrane presentation and TJ protein assembly were impaired by TMEM26&#46;</p><p id="para0040" class="elsevierStylePara elsevierViewall">In summary&#44; the present study identified the important role of TMEM26&#44; a lesser-known plasma membrane protein&#44; in the EMT of ESCC cells for the first time&#46; Although TMEM26 was elevated in ESCC&#44; no genetic evidence supporting the importance of TMEM26 in ESCC has been published&#46; Future studies will be required to identify the mutation&#44; copy number variation alteration&#44; and other types of genetic defects of TMEM26 in ESCC&#46; Besides&#44; the specific mechanism of how NF-&#954;B signaling is regulated by TMEM26 has not been elucidated in this study&#46; In the future&#44; identifying the molecule-specific regulation between NF-&#954;B signaling and TMEM26 is another important direction of the present study&#46; Regarding the TJ assembly&#44; the direct interaction between TMEM26 and TJ protein was not determined although the plasma membrane presentation and TJ protein assembly were impaired by TMEM26&#46; Thus&#44; future studies should evaluate the detailed mechanism of how TMEM26 impairs TJ assembly using biophysical methods &#40;particularly phase separation assay in the cells and with purified proteins&#41;&#46;</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Conclusion</span><p id="para0041" class="elsevierStylePara elsevierViewall">In conclusion&#44; the present study&#44; for the first time&#44; examined TMEM26 expression between tumorous and adjacent tissues from patients with ESC and demonstrated that TMEM26 expression was high in ESCC samples and cell lines&#46; The present findings identified the promotion of TMEM26 on the EMT processes of ESCC cells <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; which might rely on its role in activating NF-&#954;B signaling and disrupting TJ formation&#46; TMEM26 might be a potential therapeutic target for metastatic ESCC&#46;</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">Funding</span><p id="para0042" class="elsevierStylePara elsevierViewall">This study was financially supported by the Science and Technology Plan Project of Suzhou &#40;SZM2022009&#41; and the Horizontal Research Foundation of Soochow University &#40;P142900221&#41;&#46;</p></span><span id="sec0023a" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031a">CRediT authorship contribution statement</span><p id="para0042a" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Guohu Han&#58;</span> Conceptualization&#44; Writing &#8211; original draft&#46; <span class="elsevierStyleBold">Shuangshuang Zhou&#58;</span> Data curation&#46; <span class="elsevierStyleBold">Junjun Shen&#58;</span> Data curation&#46; <span class="elsevierStyleBold">Yuanyuan Yang&#58;</span> Data curation&#46; <span class="elsevierStyleBold">Xuyu Bian&#58;</span> Formal analysis&#46; <span class="elsevierStyleBold">Yahu Li&#58;</span> Formal analysis&#46; <span class="elsevierStyleBold">Rui Ling&#58;</span> Formal analysis&#46; <span class="elsevierStyleBold">Rongrui Liang&#58;</span> Conceptualization&#44; Writing &#8211; review &#38; editing&#46; <span class="elsevierStyleBold">Min Tao&#58;</span> Conceptualization&#44; Writing &#8211; review &#38; editing&#46;</p></span></span>"
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          "titulo" => "Highlights"
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          "titulo" => "Abstract"
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              "titulo" => "Objectives"
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            1 => array:2 [
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          "titulo" => "Keywords"
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        3 => array:2 [
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          "titulo" => "Abbreviations"
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        4 => array:2 [
          "identificador" => "sec0001"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0002"
          "titulo" => "Materials and methods"
          "secciones" => array:11 [
            0 => array:2 [
              "identificador" => "sec0003"
              "titulo" => "Cell lines&#44; reagents&#44; and antibodies"
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            1 => array:2 [
              "identificador" => "sec0004"
              "titulo" => "Patients and ESCC specimen collection"
            ]
            2 => array:2 [
              "identificador" => "sec0005"
              "titulo" => "Immunohistochemistry"
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            3 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "The liver metastatic murine model"
            ]
            4 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Cell culture and transfection"
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            5 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "MTT assay for cell viability"
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            6 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Wound healing assay"
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              "identificador" => "sec0010"
              "titulo" => "Transwell invasion assay"
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              "identificador" => "sec0011"
              "titulo" => "Western blotting"
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              "titulo" => "Immunofluorescent staining"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Elevated TMEM26 expression in ESCC"
            ]
            1 => array:2 [
              "identificador" => "sec0016"
              "titulo" => "Silencing TMEM26 blocked the EMT-associated processes of ESCC"
            ]
            2 => array:2 [
              "identificador" => "sec0017"
              "titulo" => "TMEM26 overexpression aggravated EMT-associated processes of ESCC"
            ]
            3 => array:2 [
              "identificador" => "sec0018"
              "titulo" => "TMEM26 contributes to ESCC metastasis to the liver"
            ]
            4 => array:2 [
              "identificador" => "sec0019"
              "titulo" => "TMEM26 promoted NF-&#954;B signaling and is involved in the EMT of ESCC"
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            5 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "TMEM26 impaired TJ to support EMT of ESCC"
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          "titulo" => "Discussion"
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          "titulo" => "Conclusion"
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          "identificador" => "sec0023"
          "titulo" => "Funding"
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          "identificador" => "sec0023a"
          "titulo" => "CRediT authorship contribution statement"
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        11 => array:2 [
          "identificador" => "xack769838"
          "titulo" => "Acknowledgment"
        ]
        12 => array:1 [
          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-04-21"
    "fechaAceptado" => "2023-07-31"
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      "en" => array:2 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1869100"
          "palabras" => array:4 [
            0 => "Tight junctions"
            1 => "Cell movement"
            2 => "Epithelial cells"
            3 => "Esophageal squamous cell carcinoma"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1869099"
          "palabras" => array:13 [
            0 => "EC"
            1 => "ESCC"
            2 => "EAC"
            3 => "EMT"
            4 => "KIFC3"
            5 => "TJ"
            6 => "ZO"
            7 => "TMEM26"
            8 => "PBS"
            9 => "BCA"
            10 => "FBS"
            11 => "RT"
            12 => "S&#46;D&#46;"
          ]
        ]
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    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara009" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">The involvement of TMEM26&#44; a novel plasma membrane protein&#44; in cancer EMT was examined for the first time&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">The discovery of TMEM26 and its regulation on the tight junction activates NF-&#954;B signaling as a novel therapeutic target of metastatic ESCC&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">A mechanism that directly controls the assembly of tight junctions at the plasma membrane&#44; which affects a plethora of signaling pathways&#44; was discovered&#46;</p></li></ul></p></span>"
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objectives</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">Metastasis is one of the biggest challenges in the management of Esophageal Squamous Cell Carcinoma &#40;ESCC&#41;&#44; of which molecular mechanisms remain elusive&#46; The present study aimed to explore the roles and underlying mechanisms of Transmembrane protein 26 &#40;TMEM26&#41; in ESCC&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Method</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">TMEM26 expressions in tumorous and adjacent tissues from patients with ESCC and in normal esophageal epithelial and ESCC cell lines were detected by immunostaining and western blotting&#44; respectively&#46; The Epithelial-Mesenchymal Transition &#40;EMT&#41;&#44; a critical process during metastasis&#44; was investigated by wound healing and Transwell assays&#44; and EMT-related proteins were examined after the TMEM26 alteration in ESCC cell lines&#46; NF-&#954;B signaling activation and Tight Junction &#40;TJ&#41; protein expression were analyzed by western blotting and immunofluorescence&#44; respectively&#46; <span class="elsevierStyleItalic">In vivo</span> verification was performed on the liver metastatic murine model&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">Compared with non-cancerous esophageal tissues and cells&#44; the TMEM26 expression level was higher in ESCC samples and cell lines&#44; where the plasma membrane localization of TMEM26 was observed&#46; The EMT-related processes of ESCC cells were suppressed by RNAi depletion of TMEM26 but aggravated by TMEM26 overexpression&#46; Mechanistically&#44; TMEM26 promoted NF-&#954;B signaling to accelerate EMT in ESCC cells&#46; The plasma membrane presentation and assembly of TJ proteins were impaired by TMEM26&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">Overall&#44; TMEM26 acts as a critical determinant for EMT in ESCC cells by disrupting TJ formation and promoting NF-&#954;B signaling&#44; which may be a potential therapeutic target for treating metastatic ESCC&#46;</p></span>"
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            "etiqueta" => "Appendix"
            "titulo" => "Supplementary materials"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Elevated TMEM26 expression in ESCC&#46; &#40;A&#41; Representative images of immunohistochemical staining for TMEM26 were conducted for slices from the ESCC tumor and control tissues from the same patient&#46; &#40;B&#41; A higher number of TMEM26-positive cells were quantified in the ESCC tumor tissues compared with the control tissues from the same patient&#46; Data are presented as mean &#177; S&#46;D&#46;&#44; <span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;40&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">TMEM26 expression and cellular localization in various ESCC cell lines&#46; &#40;A&#41; The abundance of TMEM26 in the normal esophageal epithelial cell line &#40;HET-1A&#41; and a collection of ESCC cell lines &#40;KYSE150&#44; KYSE270&#44; KYSE450&#44; TE4&#44; and TE8&#41; were examined by western blotting&#46; &#40;B&#41; Immunofluorescent staining of TMEM26 with DAP in KYSE270 and TE8 cells verified the plasma membrane localization of TMEM26&#46; Scale bar&#160;&#61;&#160;10&#160;&#181;m&#46;</p>"
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">TMEM26 depletion in ESCC cells suppressed EMT-related alterations&#46; &#40;A&#41; Transfection of siRNA targeting the TMEM26 gene &#40;three independent targets&#41; efficiently downregulated TMEM26 expression in TMEM26-high KYSE270 and TE8 cells&#44; as detected in western blotting&#46; &#40;B&#41; Transwell assay revealed a reduced number of invaded cells with TMEM26 RNAi&#44; compared with control RNAi&#44; in TMEM26-high KYSE270&#44; and TE8 cells&#46; Left&#58; representative images&#46; Right&#58; quantification and statistical result&#46; Scale bar&#160;&#61;&#160;100&#160;&#181;m&#46; &#40;C&#41; Wound healing assay for TMEM26 RNAi KYSE270 and TE8 cells showed fewer cells migrating into the wound region&#44; compared with control RNAi cells&#46; Left&#58; representative images&#46; Right&#58; quantification and statistical result&#46; Scale bar&#160;&#61;&#160;100&#160;&#181;m&#46; &#40;D&#41; Western blotting to detect mesenchymal and epithelial marker expressions showed downregulated twist&#44; snail&#44; N-cadherin&#44; and vimentin but upregulated E-cadherin in TMEM26 RNAi KYSE270 and TE8 cells&#46; Data are presented as means &#177; S&#46;D&#46;&#44; <span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;3&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46;</p>"
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">TMEM26 overexpression in ESCC cells promoted EMT-related alterations&#46; &#40;A&#41; Transfection of TMEM26-expressing plasmid by lentiviral vectors efficiently over-regulated TMEM26 in TMEM26-low KYSE150 and KYSE450 cells&#44; as shown by western blotting&#46; &#40;B&#41; Transwell assay showed a higher number of invaded cells with TMEM26 overexpression than with control transfection in TMEM26-low KYSE150 and KYSE450 cells&#46; Left&#58; representative images&#46; Right&#58; quantification and statistical result&#46; Scale bar&#160;&#61;&#160;100 &#181;m&#46; &#40;C&#41; The wound healing assay showed that the number of cells migrating into the wound region in TMEM26-overexpressing KYSE150 and KYSE450 cells was higher than that in control transfection cells&#46; Left&#58; representative images&#46; Right&#58; quantification and statistical result&#46; &#40;D&#41; Western blotting detection of mesenchymal and epithelial marker expressions showed upregulated twist&#44; snail&#44; N-cadherin&#44; and vimentin but downregulated E-cadherin in TMEM26-overexpressing KYSE150 and KYSE450 cells than that in control transfection cells&#46; Data are presented as means &#177; S&#46;D&#46;&#44; n&#160;&#61;&#160;3&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46;</p>"
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          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">TMEM26 did not affect ESCC cell growth&#46; &#40;A&#41; In TE8 &#40;left&#41; and KYSE270 &#40;right&#41; cells&#44; siRNA knockdown of TMEM26 &#40;three independent targets&#41; did not show observable differences in the growth curve compared with siRNA control cells&#44; as determined by MTT assay&#46; &#40;B&#41; In KYSE150 &#40;left&#41; and KYSE450 &#40;right&#41; cells&#44; TMEM26 overexpression due to lentiviral transfection did not show observable differences in the growth curve compared with control cells&#44; as determined by MTT assay&#46; Data are presented as means &#177; S&#46;D&#46;&#44; <span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;6&#46;</p>"
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Article information
ISSN: 18075932
Original language: English
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es en pt

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